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Arterio-venous transit and oxygen extraction fraction before and after blood transfusion in sickle cell disease

Tonner DeBeer¹, Lori C Jordan², Spencer Waddle¹, Chelsea A Lee², Niral J Patel², Maria Garza³, Larry Taylor Davis⁴, Sumit Pruthi⁴, Randall Sky Jones², and Manus Joseph Donahue³
¹Vanderbilt University, Nashville, TN, United States, ²Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States, ³Neurology, Vanderbilt University Medical Center, Nashville, TN, United States, ⁴Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, United States

Synopsis

Most persons with sickle cell disease (SCD) lack conventional stroke risk factors, yet nearly 50% have evidence of brain infarcts by age 30 years, indicating alternative etiologies for ischemia. We investigated whether accelerated red cell transit affects oxygen extraction and improves following transfusion-induced increases in hemoglobin. Findings suggest that evidence of accelerated capillary transit is present on arterial spin labeling (ASL) MRI, and reduces following transfusion-induced increases in hemoglobin. Furthermore, the relationship between dural ASL signal and brain oxygen extraction evolves following transfusion, suggesting that oxygen delivery is complexly dependent on blood oxygen content and capillary dynamics.

Introduction

Persons with sickle cell disease (SCD) suffer from chronic hemolytic anemia, reduced blood oxygen content, and risk of silent and overt stroke ¹. Most persons with SCD lack conventional stroke risk factors, yet nearly 50% have evidence of brain infarcts by age 30 years, indicating alternative etiologies for ischemia ^{2, 3}. As blood oxygen content reduces due to anemia, cerebral blood flow (CBF) will increase to maintain an adequate oxygen delivery to tissue. Such hyperemia is expected to improve oxygen delivery, however oxygen delivery additionally depends on the capillary transit time. For individuals in whom red cells spend sufficiently less time to traverse the capillary bed, there will be less time for oxygen extraction (Figure 1). Therefore, oxygen delivery to tissue may not scale directly with CBF but may also depend on the time the red cell spends in the capillary bed itself ^{4, 5}. We investigated whether accelerated red cell transit through capillaries, visible on arterial spin labeling (ASL) MRI, relates to reduced oxygen extraction fraction (OEF) and improves following transfusion-induced increases in hemoglobin.

Materials and Methods

Demographics. Adult and pediatric participants with SCD (HbSS or HbSβ0 phenotype) provided informed consent. SCD participants scheduled for clinically-indicated blood transfusion were enrolled; a second cohort of SCD participants stable on hydroxyurea without blood transfusion were included and scanned at two points. Experiment. 3T MRI (Philips Healthcare) was performed within seven days prior to transfusion and repeated within seven days after transfusion. Hemoglobin levels and arterial oxygen saturation were measured on the day of the scan. Pseudocontinuous arterial spin labeling (pCASL) was used to evaluate gray matter CBF and dural venous signal intensity (spatial resolution=3x3x7 mm3; adult post-labeling delay=1900 ms; children post-labeling delay=1650 ms). T2-relaxation-under-spin-tagging (TRUST) data were acquired twice per session (spatial resolution=3.4x3.4x5 mm3, tCPMG=10 ms, effective echo time=0, 40, 80, and 160 ms) for OEF determination ⁶. Analysis. pCASL data were corrected for hematocrit and labeling efficiency. Dural signal was evaluated in the pCASL data in two ways: (i) using a previously reported categorical consensus (2-rater) scoring system ⁵ and (ii) using a continuous, quantitative measure of venous signal at a standardized location in the superior sagittal sinus at the location of the parieto-occipital sulcus. Venous blood water T2 was quantified in the superior sagittal sinus from TRUST and converted to venous oxygen saturation using models that have a hematocrit dependence and are calibrated over an anemic range: human hemoglobin-AA, human hemoglobin-F, and a model that merged SCD data from two different studies ^7-9. Hypothesis testing. Paired statistics were calculated between pre-transfusion and post-transfusion and between time-1 and time-2 using paired t-tests for parametric data. A Wilcoxon test was applied to nonparametric data in the SCD transfused and SCD non-transfused participants to determine group differences between OEF and both CBF in tissue and flow signal (significance: two-sided p<0.05).

Results

We enrolled 32 transfused SCD participants (age=18.2 ± 9.1 years, 53% male) and 13 non-transfused SCD participants (age=21.2 ± 8.0 years, 38% male) and (Table 1). Figure 2 shows three SCD participants, each with different categorical shunting scores according to previously published criteria. Using the categorical scoring system, no difference in mean shunting scores between time points was observed. However, for the more sensitive continuous measure, we observed no significant difference in mean flow signal between time-1 (117.4±30.1 ml/100g/min) and time-2 (117.1±32.1 ml/100g/min) of non-transfused participants (p=0.650), yet in transfused participants a significant decrease in mean flow signal was observed between pre-transfusion (113.6±37.1 ml/100g/min) and post-transfusion (98.9±33.9 ml/100g/min) (p=0.034) (Figure 3). We observed that with increasing mean dural sinus flow signal, consistent with increased capillary shunting, participants before transfusion had a reduced OEF (Wilcoxon test, p=0.011). This relationship between OEF and flow signal reversed post-transfusion when using the HbF or HbAA models (p<0.01), or became non-significant (p=0.905) when using the merged-mixture model.

Discussion

We provide evidence that arterio-venous shunting, visualized as dural sinus hyperintensity on arterial spin labeling MRI, reduces following transfusion-induced increases in hemoglobin in adults and children with SCD. We extend other preliminary findings ¹⁰ to demonstrate this effect, and its relation to oxygen extraction, in a larger cohort of SCD participants before and after transfusion. Prior to transfusion, an inverse correspondence between dural sinus hyperintense signal and global OEF was observed; after transfusion, this relationship changed and was either null or positive, depending on calibration model used. Results provide evidence of such shunting contrast reducing following transfusion, and this corresponds with a change in the relationship between the dural sinus signal and OEF.

Conclusion

This study utilizes novel multi-modal functional hemodynamic MRI to provide evidence that capillary transit time is associated with oxygen extraction efficiency in participants with SCD, and importantly that transfusion-induced increases in hemoglobin yield imaging contrast consisted with a lengthening of these capillary transit times.

Acknowledgements

Funding provided by NIH/NHLBI 5K24HL147017, NIH/NINDS 5R01NS096127, and NIH/NINDS 5R01NS097763

References

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Figures

Table 1. Participant demographics and measures of rapid arterio-venous transit in SCD participants with and without transfusion.

Figure 1. (A) In healthy brain parenchyma, capillary transit times of 1-1.5s lead to an OEF of 30–40%. (B) In compensated anemia, smooth muscle facilitates arteriolar vasodilation and increase blood flow; when these changes are sufficient to maintain cerebral oxygen delivery despite anemia, normal amounts of oxygen are delivered to tissue. (C) In non-compensated anemia, the cerebral hyperemic response might lead to a rapid transit of blood through capillaries (white arrows). This rapid transit might result in insufficient time for oxygen to be extracted by tissue.

Figure 2. Continuous (A) and a categorical (B, C, D) evaluations of dural signal. (E) Male on regular blood transfusion therapy. Pre-transfusion whole-brain OEF (model) is 32.6%, which reduces post-transfusion to 33.8%. Pre-transfusion dural sinus flow signal is 121.8 ml/100g/min, which reduces post-transfusion to 65.3 ml/100g/min. (F) A male in whom whole-brain OEF is 29.7% at baseline, which slightly increases at time-2 to 30.4%. Mean flow signal in dural sinus does not change significantly between timepoints.

Figure 3. In SCD participants not receiving transfusion, (A) CBF and (B) sagittal sinus flow signal are similar at two time points. In participants receiving interval transfusion, (A) CBF and (B) flow signal in the sagittal sinus both reduce. (C) Before transfusion, there is an inverse relationship between flow signal in the sagittal sinus and OEF, whereas after transfusion the relationship becomes positive. (D) OEF calculated from different available models (HbF, HbAA, and merged mixture model) are significantly correlated (p<0.001), however yield different mean values.

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)

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DOI: https://doi.org/10.58530/2022/0810